Chapter 4 Mood disorders

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1 Chapter 4 Mood disorders Depressive disorder Epidemiology Aetiology OSCE grid Assess depressive disorder Compare ICD-10 and DSM-IV-TR criteria Differential diagnosis, investigation and questionnaire Management Antidepressants Electroconvulsive therapy OSCE video Explain ECT Psychotherapy Course and prognosis Bipolar disorder Epidemiology Aetiology ICD-10 and DSM-IV-TR criteria OSCE grid Assess manic symptoms Investigations and questionnaire Management (MOH and NICE guidelines) Mood stabilisers OSCE video Explain lithium side effects Suicide and deliberate self harm Bereavement, abnormal grief, seasonal affective disorder. Revision MCQs and MEQs Depressive disorder Epidemiology Incidence International 14.0 per 1000 persons Lifetime prevalence Overall: 10-20%; 1 in 4 women and 1 in 10 men have depressive disorder in their lifetime. Point prevalence Age of onset Gender ratio 2-5% years F:M = 2:1 Singapore As above As above 5.6% As above As above Aetiology Genetics: 1) Family studies show that a person has 40-70% chance to develop depressive episode if a first degree relative suffer from depressive episode. 2) Twin studies show that the concordance rate for monozygotic twins is 40 50% and for dizygotic twins is 20%. 3) Adoption studies show that the risk to develop depressive disorder of adoptees with family history of depressive disorder is twice as high as in adoptees without family history of depressive disorder. Organic causes: 1) Physical illnesses include Cushing s syndrome, Addison s disease, Parkinson s disease, stroke, epilepsy, coronary arterial disease and hypothyroidism 2) Medications: Corticosteroids, oral contraceptive pills, beta-blockers, clonidine, metoclopramide, theophylline and nifedipine Psychosocial factors: (a) Adversity in childhood Maternal loss and disruption of bonding. Poor parental care and over-protection among parents. Childhood physical and sexual abuse. (b) Adversity in adulthood Women: Absence of a confiding relationship, having more than 3 children under the age of 14 and unemployment (Brown and Harris social origins of depression, 1978). Men: Unemployment, divorce (e.g. unable to pay for maintenance fees and loss of custody). Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 1

2 (c ) Recent life events Loss of a child. Death of a spouse. Divorce. Martial separation. Imprisonment. Recent death of a close family member. Unemployment. Neurobiology of depressive disorder: 1. Monoamine theory states that depressed patients have decreased levels of noradrenaline, serotonin and dopamine. Evidence include the finding that the 5-HIAA levels are reduced in the CSF of depressed patients who committed suicide. 5-HIAA is a metabolite of serotonin. The tricyclic antidepressants increase noradrenaline levels. The selective serotonin reuptake inhibitors increase the serotonin levels. The antidepressant bupoprion may increase dopamine levels. 2. Other neurotransmitters include raised acetylcholine levels (associated with depressive symptoms such as anergia, lethargy, psychomotor retardation) and decreased levels of gamma-aminobutyic acid (GABA). 3. Neuroendocrinology: Elevated CRF, ACTH and cortisol in blood and CSF in depressed patients. Non-suppression in dexamethasone suppression test (DST) is greatest in people with severe depression and reversed with antidepressant treatment. Non-suppression of DST is a result of increased hypothalamic CRF release. Depression reduces the level of inhibitory hormone, somatostatin and increases the level of growth hormone. Decreased levels of thyroid hormone (T 4 ) are associated with depressive symptoms. 4. Neuroimaging: Ventricular enlargement, sulcal widening and reduction in size in the frontal lobe, cerebellum, basal ganglia, hippocampus and amygdala. ICD-10 and DSM-IV-TR criteria Summary of ICD-10 F32.0 Mild, F32.1 Moderate, F32.2 Severe (Bold + Italic) criteria) diagnostic criteria of depressive disorder in four axes (RATA). The RATA axis: Reality (hallucinations and delusions); Appearance and behaviour; Thought and speech; Affect and interest. General appearance : - Not specified by ICD 10 or DSM IV TR - Neglect of dressing & grooming - Turning downwards of the corners of the mouth - Vertical furrowing of the centre of brow & gaze is downwards Hallucination Condemnatory auditory hallucinations Appearance - behaviour axis Reality axis Thoughts : 1. Recurrent thoughts of death or suicide 2. Diminished ability to think and concentrate Thoughtspeech axis DEPRESSIVE DISORDER Affect: 1. Depressed mood most of the day, almost every day for 2 weeks (CORE criteria) Affectinterest axis Delusion 1. Guilt 2. Hypochondriasis 3. Nihilistic 4. Self referential 5. Persecutory Interest 1. Loss of interest or pleasure in activities that are normally pleasurable (CORE criteria) 2. Decreased energy or increased fatigability (CORE criteria) Speech Depressive stupor Behaviour 1. Loss of confidence or self esteem 2. Unreasonable feelings of self reproach or excessive guilty 3. Psychomotor agitation or retardation 4. Sleep disturbance 5. Change in appetite 6. Somatic syndrome Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 2

3 For ICD 10, mild depressive disorder requires 2 out of 3 core criteria + 2 remaining criteria; moderate depressive disorder requires 2 out of 3 core criteria + 4 remaining criteria; severe depressive disorder requires 3 out of 3 core criteria + 6 remaining criteria + psychotic features. Other criteria for DSM-IV TR Major Depressive Episode include weight loss; significant distress in social and occupational functioning; not due to substance, medical condition, or bereavement. OSCE grid: Assess depression. You are the resident working in the AED. A 30 year - old teacher is referred by polyclinic for management of depression. He cannot cope with the workload and he also has interpersonal problems with the school principal. Task: To a history to establish the diagnosis of depressive disorder. Please note that forgetting to have a brief assessment of suicidal risk in a depressed patient may result in a failure. A. Assess core symptoms of depression. A1) Assess mood. During the past month, how often have you been bothered by feeling down or depressed? Can you rate your current mood from a scale of 1 to 10? 1 means very depressed and 10 means very happy. Which part of the day is the worst? (Elicit diurnal variation of mood) A2) Assess energy level. Have your energy levels been recently? Do you feel tired most of the time? A3) Assess interest. Can you tell me more about your interests and hobbies before the current depressive episode? During the past month, how often have you been bothered by having little interest or pleasure in doing things? B. Assess biological symptoms of depression. B1. Assess sleep. How has your sleep been lately? Can you fall asleep? If not, how long does it take? How many times do you wake up in the middle of the night? (exclude urination) What time do you wake up in the morning? (look for early morning wakening). If you wake up, can you fall asleep again? B2. Assess appetite and weight. Has your appetite changed recently? If yes, do you tend to eat less or more? Has your weight changed recently? If so, have you lost weight or gained weight. If yes, how many kilograms were involved? B3.Assess sexual functions. I hope you would not mind if I ask you some sensitive questions such as sexual problems as depression may affect sexual function. Is it OK with you? Have there been any changes in your sexual function recently? If yes, can you tell me more about the nature of sexual dysfunction? When did the sexual dysfunction start? (Does it coincide with the onset of depression?) C. Assess cognitive symptoms. C1. Assess cognitive impairment. What has your concentration been like recently? Can you concentrate when you teach? C2. Assess feelings towards self and future. How do you see yourself? Do you see yourself a failure? C3. Explore common cognitive bias. Can you tell me more about your negative thoughts? Look for selective abstraction, Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 3

4 How has your memory been? How do you see your future? Do you feel hopeless? overgeneralization or catastrophes thinking. Depending on the patient s response, you may gently challenge patient s belief or provide an alternative explanation to seek his or her view? D. Assess risk, psychotic features, insight. D1. Assess suicide risk. Have you felt that life is not worth living? Would you do anything to harm yourself or hurt yourself? Have you done anything of that sort? Have you made any plans? Have your told anybody about it? D2. Assess psychotic features. When people are under stress, they complain of hearing voices or believing that other people are doing something to harm him. Do you have such experiences? D3. Assess insight What is your view of the current problem? Do you think that you may suffer from a depressive illness? E. Explore causes and background. E1. Explore family history of depression. Do you have any biologically related relative suffer from depression? Do you have any biologically related relative attempt or commit suicide in the past? E2. Explore past psychiatric history and relevant medical illnesses. Did you seek help from a psychiatrist or GP in the past for your low mood? Did you receive any treatment from a psychiatrist? If yes, can you tell me more about the medication and side effects? E3. Assess support system. Can you tell me the person who is providing emotional support to you at this moment? Is there a person in the school whom you can talk to? What is your career plan at this moment? How anxious do you feel in yourself? (explore comorbidity) Have you sought help from Ministry of Education? Do you drink alcohol on a daily basis to cope with stress or help you to sleep? Do you suffer from any chronic medical illness? Compare and contrast ICD-10 and DSM-IV criteria for depressive disorder Summary other types of depressive disorder in ICD-10 & DSM-IV-TR ICD 10 DSM IV Severity of depressive illness Mild depressive episode. Moderate depressive episode with or without somatic symptoms Severe depressive episode with or without psychotic symptoms. Major depressive disorder single or recurrent episode. Mild, moderate, severe without psychotic or with psychotic features. With catatonic features With postpartum onset. Recurrent At least one episode of mild, moderate & severe Separate mood episodes with an interval of at least 2 Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 4

5 depressive disorder Cyclothymia Dysthymia Other mood disorders Melancholic depression Atypical features depression lasting 2 weeks and separate from the current episode by at least 2 months. Recurrent episodes of depressive reaction, psychogenic, reactive and seasonal depressive disorder. No history of manic or hypomanic episode. It often associates with short period of anxiety and risk for deliberate self harm. A persistent instability (2 years) of mood involving numerous periods of depression and mild elation but not severe for diagnosis of bipolar disorder or depressive disorder. Some people have cyclothymic personality. There must be a period of at least 2 years of constant or constantly recurring depressed mood while normal mood rarely lasts longer than a few weeks. Rapid alternation of hypomanic, manic or depressive symptoms within a few hours for at least 2 weeks. Recurrent brief depressive disorder which lasts less than 2 weeks. Not mentioned Not mentioned consecutive months. Recurrent with catatonic, melancholic, atypical features or postpartum onset. At least 2 years for adult, 1 year for children & adolescents. Similar to ICD 10 criteria At least 2 years for adult, 1 year for children & adolescents. Poor appetite/overeating; insomnia/ hypersomnia, fatigue, low self esteem, poor concentration, hopelessness. Early onset < 21 years. Later onset > 21 years. Chronic depression: at least 2 years. Longitudinal course: with or without inter-episode recovery. 1) Loss of pleasure in all activities. 2) Lack of reactivity to usually pleasurable stimuli. 3) Distinct quality of depressed mood. 4) Depression regularly worse in the morning. 5) Early morning awakening. 6) Marked psychomotor retardation. 7) Significant anorexia and weight loss. 8) Excessive or inappropriate guilt. Duration: 2 weeks 1) Mood brightens in response to actual or potentially positive events. 2) Hypersomnia. 3) Leaden paralysis in arms or legs. 4) Long standing pattern of interpersonal rejection sensitivity. Differential diagnosis Differential diagnosis of depressive disorder include: 1. Adjustment disorder, dysthymia, bipolar disorder, eating disorders, schizoaffective disorder, schizophrenia with predominance of negative symptoms. 2. Dementia, Parkinson s disease, post-stroke depression and head injury in old people presenting with depression.. 3. Addison s disease, Cushing s disease, hypothyroidism, parathyroid dysfunction, hypopituitarism and menopausal symptoms.. 4. Systemic lupus erythematosus. Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 5

6 Investigation 5. Syphilis and HIV encephalopathy. 6. Medication induced (e.g. beta-blockers, steroids, oral contraceptive pills) 7. Substance misuse (e.g. benzodiazepines, alcohol and opiates). Routine laboratory tests should be ordered (e.g. FBC, ESR, B12/Folate, RFT, LFT, TFT, calcium panel and PTH). Sodium level is important in elderly who are prone to hyponatraemia as a result of SSRI treatment. Further investigations include urine drug screen, urine FEME and urine culture (for elderly), thyroid antibodies (for people with abnormal TFT), antinuclear antibody (suspected SLE), syphilis Serology, HIV testing, CT/MRI. Questionnaire Beck Depression Inventory (BDI) The BDI is a 21-item self rate instrument to measure the presence and degree of depression in both adolescents (Reading age of approximately 10 years is required) and adults. It is self-rated and was designed to measure attitude and symptoms characteristic of depression. The BDI covers the 2 weeks prior to evaluation. It consists of 21 items, each categorised into various level of severity (with a range of score from 0 to 3). The total score is the sum of items. A total score <9 indicates no or minimal depression. A total score >30 indicates severe depression. Hamilton depression scale (HAM-D) The HAM-D scale is a clinician rated semi-structured scale. It is designed to measure the severity of depressive symptoms in patients with primary depressive illness. It has two versions: 17-item scale and 21-items scale. The 17-item version covers mood, suicide, guilt, sleep, appetite, energy, somatic complaints, sexual function and weight. The 21-item consists of addition 4 items on diurnal variation of mood, derealisation / depersonalisation, paranoid idea and obsession / compulsions. The HAM-D scale monitors changes in the severity of symptoms during treatment. The HAM-D scale is not diagnostic and its validity is affected if the person has concurrent physical illness. The total scores range from 0 (no depression), 0-10 (mild depression), (moderate depression) and over 23 (severe depression). Montgomery-Asberg Depression Rating Scale (MADRS) The MADRS is a clinician-rated scale for patients with major depressive disorder. It measures the degree of severity of depressive symptoms and is a particularly sensitive measure of change in symptom severity during treatment. The 10-item checklist measures current mood state. In contrast to HAM-D, the MADRS is useful for people with concurrent physical illness as it puts less emphasis on somatic symptoms. Management [Mahendran and Yap (2005) and NICE guidelines (UK)) Goal The goal of treatment is to achieve symptomatic remission of all signs and symptoms of depression, restore occupational and psychosocial functioning, Initial treatment Counselling and supportive therapy alone may benefit those patients with mild depression. If sleep is a problem, doctor should offer sleep hygiene advice. If antidepressants are used as the first line of treatment, SSRI is the first line treatment. Tricyclic antidepressants (TCAs) must be avoided in suicidal patients because of their lethality in overdose. Doctors need to inform patient that the antidepressants will take 4 to 6 weeks to achieve its effect. Doctors should be familiar with side effects and be able to explain to patients about the side effects. Monotherapy with a single antidepressant is recommended. In patients who are reluctant to start antidepressants, or patients with comorbid medical conditions who may be unable to tolerate the antidepressants, psychotherapy may be considered as a first-line treatment. Hospitalisation may be required if the patient poses high suicide risk to self. Acute phase of treatment The acute phase of treatment is accepted as lasting 12 weeks. Efficacy of the treatment is gauged by amelioration of symptoms and the dose should be titrated according to clinical response. Monitor all patients recently started on antidepressants closely for increased agitation and suicidal behaviour, especially young patients (younger than 25 years). Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 6

7 Stabilisation phase Some symptoms, such as sleep and appetite, may improve more quickly. If partial response or non-response, increase the dose or switch to another antidepressant. The first line is an alternative SSRI. The second line is an antidepressant from a different class. Doctors have to consider the half-life of the antidepressant before switching. A washout period is needed when switching from fluoxetine which has a long half-life and moclobemide (reversible MAOI) which requires a three-day washout period. If there is inadequate response to a single drug treatment, other agents such as another antidepressant (e.g. mirtazapine), mood stabiliser (e.g. lithium) or antipsychotics (e.g. olanzapine) can be added as augmentation therapy. Combination with psychotherapy such as cognitive behaviour therapy is recommended for patients with moderate depressive episode. Antidepressants should be continued for at least six months after the acute phase. 3 to 4 months of psychological intervention is recommended for mild depressive episode. 4 to 6 months of psychological intervention is recommended for moderate and severe depressive episode. If a patient needs to stop antidepressants, stop gradually over a four-week period to avoid discontinuation symptoms. Common discontinuation symptoms include anxiety, giddiness, flu like symptoms, low mood nausea and insomnia. Antidepressants with shorter half live such as paroxetine and venlafaxine need to discontinue over a longer of time. Selective serotonin reuptake inhibitors (SSRIs) Indications Contraindications Mechanism of action Side effects Depressive disorder (first line treatment, less sedative than TCAs). Mania Anxiety disorders Obsessive compulsive disorder Bulimia nervosa (fluoxetine) Premature ejaculation. Common SSRIs used in Singapore (2012 price in SGD) SSRIs selectively block reuptake of serotonin at presynaptic nerve terminals and increase synaptic serotonin concentrations Fluoxetine [Prozac] (Dose range: 20 60mg/day; $0.46 for 10mg and $0.24 for 20mg) Special features 1) Non linear elimination kinetics 2) safe in overdose. Nausea, abdominal pain, diarrhoea, constipation, weight loss. Agitation, tremor or insomnia. Sexual dysfunction Other indications: 1) OCD (>60mg/day); 2) Panic disorder; 3) Bulimia Nervosa; 4) PTSD; 5) Premenstrual dysphoric disorder; 6) Premature ejaculation and 7) Childhood & adolescent depression. Pharmacokinetics: 1) Fluoxetine inhibits the P450 3A3/4, 2C9, 2C19 & 2D6 and it also inhibits its own metabolism. 2) Due to non-linear pharmacokinetics, higher doses can result in disproportionately high plasma levels and of some sideeffects (e.g. sedation) rather late in the course of treatment with this drug. Its metabolite norfluoxetine is much less potent. Long t 1/2 = 72 hr. Pharmacodynamics: The serotonin system exerts tonic inhibition on the central dopaminergic system. Thus, fluoxetine might diminish dopaminergic transmission leading to EPSE. Side effects: 1) Anxiety, agitation 2) Delayed ejaculation/orgasmic impotence 3) Hypersomnolence (high doses) 4) Nausea 5) Dry mouth. Drug interaction: 1) The washout period for fluoxetine before taking MAOI is 5 weeks. 2) Through inhibition of P450 Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 7

8 2D6, fluoxetine may elevate the concentration of other drugs especially those with narrow therapeutic index such as flecainide, quinidine, carbamazepine and TCAs. Fluvoxamine [Faverin] (Dose range: mg/day; $0.24 for 50mg) Special features: 1) Highly selective SSRI 2) FDA approval for OCD 3) Lower volume of distribution, low protein binding and much shorter elimination half-life compared to SSRI. Other indications: 1) Efficacious for social phobia 2) Panic Disorder 3) PTSD Pharmacokinetics: 1) Well absorbed 2) t 1/2 =19 hours 3) metabolized to inactive metabolites. 4) lower volume of distribution and low protein binding 5) maximum plasma concentration is dose dependent. 6) Steady-state levels is 2 to 4- fold higher in children than in adolescents especially females. 7) Well tolerated in old people and in people with mild cardiovascular disease or epilepsy. 8) It offers potent inhibition of P450 1A2. Pharmacodynamics: The specificity for 5HT re-uptake is greater for other SSRIs. Two neuro-adaptive changes: 1) specific serotonin receptor subtypes that change following presynaptic blockade 2) neurogenesis of hippocampal brain cells occurs and results in changes in behaviour. Side effect: 1) Nausea more common than other SSRIs; 2) Sexual side effects with fluvoxamine are similar in frequency to those with other SSRls; 3) It minimal effects on psychomotor and cognitive function in humans. Sertraline [Zoloft] (Dose range: mg/day; $1.92 for 25mg) Special features: 1) For young women with mood disorders. 2) For mood and anxiety disorders. Other indications: 1) Premenstrual dysphoric disorder 2) OCD 3) PTSD Pharmacokinetics: 1) It inhibits P450 2C9, 2C19, 2D6, 3A4. 2) t 1/2 is hours 3) More than 95% protein bound 4) Its metabolite, desmethylsertraline, is one-tenth as active as sertraline in blocking reuptake of serotonin. Pharmacodynamics: The immediate effect of sertraline is to decrease neuronal firing rates. This is followed by normalization and an increase in firing rates, as autoreceptors are desensitized. Side effects: 1)GI side effects 27%; 2) headache 26%; 3)Insomnia 22%; 4) Dry mouth 15% ; 5) Ejaculation failure 14%. Paroxetine CR [Seroxat CR] (Dose range: 12,5-50mg/day; $2.23 for 12.5mg; $2.17 for 25mg) Special features: 1) Most sedative and anticholinergic SSRI; 2 Risk of foetal exposure resulting in pulmonary hypertension Other indications: 1) Mixed anxiety and depression; 2) Panic disorder; 3) social anxiety disorder; 4) generalised anxiety disorder 5) Post-traumatic stress disorder; 6) Premenstrual disorder Pharmacokinetics: 1) Paroxetine is well absorbed from the GI tract. 2) it is a highly lipidophilic compound. 3) It has a high volume of distribution. 4) It is 95% bound to serum proteins. 4) It undergoes extensive first pass metabolism. 5) Paroxetine CR slows absorption and delay the release for 5 hours. 6)The Short t 1/2 of original paroxetine leads to discontinuation syndrome 7) It inhibits its own metabolism. Side effects: 1) Anticholinergic side effects 2) Nausea 3) Sexual side effects emerge in a dose-dependent fashion 4) Closed angle glaucoma (acute). MOH guidelines state that first-trimester paroxetine use should be avoided, as it is associated with increased risk of serious congenital (particularly cardiac) defects. Drug interaction: 1) Clinically significant interaction: MAOI, TCA, Type 1C antiarrhythmics, 2) Probably significant interaction: β-adrenergic antagonists, antiepileptic agents, cimetidine, typical antipsychotics, warfarin. Escitalopram [Lexapro] (Dose range: 10-20mg/day; $1.5 for10mg; $3.8 for 20 mg) Special features:1) Most selective SSRI 2) Relatively weak inhibition of liver P450 enzymes. 3) Escitalopram has fewer Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 8

9 side effects, more potent, shorter t 1/2, less likely to inhibit P450 system, more selective than citalopram. Other indications: 1) OCD 2) Panic Disorder 3) CVA 4) Anxiety with major depression 5) Emotional problems associated with dementia Pharmacokinetics: 1) Escitalopram is well absorbed after oral administration with high bioavailability. 2) Peak plasma concentration is normally observed 2-4 hours following an oral dose. 3) It is subject to very little first-pass metabolism. Side effects: Nausea and vomiting (20%), increased sweating (18%), dry mouth & headache (I7%), anorgasmia and ejaculatory failure, but no significant effect on cardiac conduction and repolarisation. Trazodone (Dose range: mg/day; this drug is not available at NUH) Special features: trazodone is a mixed serotonin antagonist/agonist. Pharmacokinetics: 1) Trazodone is well absorbed after oral administration, with peak blood levels occurring about 1 hour after dosing. 2) Elimination is biphasic, consisting of an initial phase (t 1/2 =4 hrs) followed by a slower phase, with t 1/2 = 7 hours. 3) Its metabolites, mcpp, is a non-selective serotonin receptor agonist with anxiogenic properties. Pharmacodynamics: Trazodone antagonises both α 1 and α 2 adrenoceptors but has very weak anticholinergic side-effects. Side effects: 1) Priapism 2) Orthostatic hypotension 3) Increased libido 4) Sedation 5) Bone marrow suppression. Noradenaline Specific Serotonin Antidepressant (NaSSa) Mirtazapine (Dose range: 15-45mg/day; $ 0.60/15mg) Special features: 1) Mirtazapine blocks negative feedback of noradrenaline on presynaptic α 2 receptors and activates noradrenaline system; 2) Mirtazapine stimulates serotonin neuron and increases noradrenaline activity; 3) Mirtazapine has no effects on seizure threshold or on cardiovascular system. 4) Suitable for patients who cannot tolerate SSRI induced sexual dysfunction.. Other indications: insomnia or poor appetite, dysthymia (40% reduction), PTSD (50% reduction) and chronic pain. Pharmacokinetics: 1) The peak plasma level is obtained after approximately 2 hours. 2) Linear pharmacokinetics and a steady-state plasma level is obtained after 5 days. 3) The elimination t 1/2 is 22 hours 4) Metabolised by P450 1A2, 2D6, and 3A4 4) 75% excreted by the kidney and 15% excreted by GI tract. Pharmacodynamics: 1) Blockade of release-modulating α 2 -adrenoceptors leads to enhanced noradrenaline release 2) the released noradrenaline stimulates serotonin neurons via the activation of α 1 adrenoceptors which in turn results in an enhanced noradrenaline effect, together with the selective activation of 5-HT 1A receptors, may underlie the antidepressant activity; 3) 5HT 1A agonism: antidepressant and anxiolytic effects. 4) 5HT 2A antagonism: anxiolytic, sleep restoring and no sexual restoration 5) 5HT 2c antagonism: anxiolytic & weight gain 6) 5HT 3 antagonism: no nausea, no gastrointestinal side effects. It also blocks histaminergic receptors and results in drowsiness. Side effects: 1) drowsiness, 2) weight gain, 3) increased appetite, 4) dry mouth, 5) postural hypotension. Serotonin noradrenaline reuptake inhibitors (SNRIs) Venlafaxine XR [Efexor XR] (Dose range: 75mg 375mg/day; $ 0.96/ 75mg tablet) Special features: Low doses of venlafaxine blocks serotonin reuptake. Moderate doses of venlafaxine block noradrenaline reuptake. High dose of venlafaxine block noradrenaline, dopamine and serotonin reuptake. 2) Metabolised by P450 3A4 to inactive metabolites while P450 2D6 to active metabolites 3) More rapid onset action and enhanced efficacy in severe depression Other indications: generalised anxiety disorder. Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 9

10 Pharmacokinetics: 1) minimally protein bound (<30%) 2) renal elimination is the primary route of excretion 3) the original version (venlafaxine) has relatively short t 1/2 = 5-7 hours; 4) prominent discontinuation syndrome (dizziness, dry mouth, insomnia, nausea, sweating, anorexia, diarrhoea, somnolence and sensory disturbance) and hence venlafaxine extended release (XR) is available. Side effects: 1) nausea (35%); 2) sustained hypertension is dose related and 50% remitted spontaneously 4) dry mouth, constipation, 5) sexual dysfunction Drug interaction: The toxic interaction with MAOIs, leading to a serotonin syndrome, is the most severe drug interaction involving venlafaxine. Duloxetine [Cymbalta] (Dose range: mg/day; $3.8/ 30mg tablet) Other indications: 1) Depression and chronic pain; 2) Fibromyalgia Pharmacokinetics: Blood levels of duloxetine are most likely to be increased when it is co-administered with drugs that potently inhibit cytochrome P450 1A2. Pharmacodynamics: Duloxetine exerts a more marked influence on noradrenaline reuptake than on serotonin reuptake. Side effects 1) Nausea, dry mouth, dizziness, headache, somnolence, constipation and fatigue are common. 2) A small but significant increase in heart rate was observed 3) Rate of sexual dysfunction is low. Tricyclic antidepressants (TCA) Indications Contraindications Mechanism of action Side effects Examples TCA is an old antidepressant and it is not first-line antidepressant treatment due to potential cardiotoxicity if patient takes an overdose. Cardiac diseases (e.g. post myocardial infarction, arrhythmias) Epilepsy Severe liver disease TCA inhibits the reuptake of both serotonin and noradrenaline and increase the concentration of these neurotransmitters. Anticholinergic (e.g. constipation, blurred vision, urinary retention, dry mouth). α-adrenergic (e.g. dizziness, syncope, postural hypotension, sedation). Depression Anxiety disorder Severe OCD (Clomipramine) Neuropathic pain Migraine prophylaxis Enuresis Prostate hypertrophy Mania TCA also blocks histaminergic H 1, α- adrenergic and cholinergic muscarinic receptors on the postsynaptic membrane. Histaminergic and dopaminergic blockade: nausea, vomiting, weight gain, sedation, Other side effects: sexual dysfunction, hyponatraemia Cardiac: arrhythmias, ECG changes (QTc prolongation), tachycardia, heart block TCA overdoses may lead to delayed ventricular conduction time, dilated pupils and acidaemia due to central respiratory depression and a fall in ph reducing protein Amitriptyline (25mg to 150mg daily) has the most potent anticholinergic effect. Clomipramine ( mg daily): Most potent TCA at D 2 receptors; More selective inhibitor of serotonin reuptake.. Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 10

11 binding. Monoamine oxidase inhibitors (MAOIs) Reversible MAOI Moclobemide (Dose range: 75mg to 225mg daily; $0.45 per 150mg tablet) Indications Contraindications Mechanism of action Side effects Atypical depression. Acute confusional state. Monoamine oxidase A acts on Visual changes. Noradrenaline Headache. Depression with Phaeochromocytoma. Serotonin Dry mouth. predominantly anxiety Dopamine Dizziness. symptoms (e.g. social Tyramine GI symptoms. anxiety). Hypochondriasis. The old irreversible MAOIs may lead to hypertensive crisis with food containing tyramine. Irreversible MAOIs are seldom used nowadays. The following food should be avoided : 1) Alcohol: avoid Chianti wine and vermouth but red wine <120 ml has little risk. 2) Banana skin. 3) Bean curds especially fermented bean curds. 4) Cheeses (e.g. Mature Stilton) should be avoided but cream cheese and cottage cheese have low risk. 5) Caviar. 6) Extracts from meats & yeasts should be avoided but fresh meat and yeast. Other antidepressants Bupropion [Wellbutrin] (Dose range: mg/day; $1.6 / 150mg tablet) Similar efficacy as SSRI but voluntary withdrawal in the US due to induction of seizure at doses if the daily dose is higher than 450mg/day. Other indications include patients encountering SSRI induced sexual dysfunction, female depressed patients do not want weight gain from medication and smoking cessation. Pharmacodynamics: blocking dopamine reuptake. Side effects: agitation, tremor, insomnia, weight loss and seizure. Bupoprion is not associated with sexual side effect. Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 11

12 Electroconvulsive therapy (ECT) Indications: 1) Severe depressive disorder which does not respond to an adequate trial of antidepressants. 2)Life threatening depressive illness (e.g. high suicide risk). 3) Stupor or catatonia 4) Marked psychomotor retardation 5) Psychotic depression 6) Treatment resistant mania 7) Treatment resistant schizophrenia. Relative contraindications: 1) Raised intracranial pressure 2) Myocardial infarction 3) Valvular heart diseases 4) Aneurysm 5) Recent stroke 6) Peptic ulcer. Mechanism of actions: 1) Release of noradrenaline, serotonin, dopamine but reduction of acetylcholine release. 2) Increase in permeability of the blood-brain barrier. 3) Modulation of neurotransmitter receptors such as GABA or acetylcholine. Administration: 1. Usually bilateral temporal ECTs for adults for 6 treatments (3 times a week). 2. Unilateral ECT is reserved for old patients with the risk of cognitive impairment. 3. Bilateral ECT is more effective than unilateral ECT. 4. An informed consent is required prior to the ECT. A second opinion from another consultant psychiatrist is required for patient who lacks capacity or in cases of patient under Mental Disorder and Treatment Act who refuses treatment. 5. ECT is given under general anaesthesia. Muscle relaxant is given to prevent muscular spasms. 6. Electric current generates a seizure for less than one minute. 7. Before ECT, avoid long acting benzodiazepine which will affect the duration of seizure. 8. After ECT, patient is recommended to continue antidepressant for at least 6 months. Side effects: Common side effects include headache, muscle pain, jaw pain, drowsiness, loss of recent memories (retrograde amnesia), anterograde amnesia (less common than retrograde amnesia), prolonged seizures (longer than 1 minute) and confusion after ECTs. Other side effects include anaesthesia complications arrhythmia, pulmonary embolism and aspiration pneumonia. Factors increase seizure threshold: old age, male gender, baldness, Paget s disease, dehydration, previous ECT and benzodiazepine treatment. Factors decrease seizure threshold: caffeine, low CO 2 saturation of blood, hyperventilation and theophylline Electrode positioning in unilateral ECT First electrode: 4cm above the midpoint of lateral angle of eye & external auditory meatus Second electrode or d Elia positioning: second electrode is placed in the midpoint of the arc. The radius of arc is around 18 cm. Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 12

13 OSCE video Explain ECT ( Refer to Clinical OSCE Videos) You are the resident and you have admitted an elderly woman suffering from severe depressive episode with delusion of guilt. She does not respond to the antidepressant and antipsychotic drug. Your consultant has recommended ECT and her daughter is very concerned and wants to speak to you. Task: Talk to her daughter and address her concerns. Approach: Express empathy. (e.g. I can imagine the idea of ECT sounds very scary for you, and it s clear you want the best care for your mother. I would like to discuss what ECT involves, because it is very different than what is portrayed in the media. This way, you can make an informed decision) Core information about ECT: ECT involves inducing a fit, while the patient is under general anaesthesia. ECT is the most effective treatment for depression, particularly for those who have high risk of suicide, very poor appetite and not responding to oral medication; sometimes in pregnant women because it has no side effects to the foetus. It is very safe and has been with us for the past 50 years. Will my mother be awake during ECT? No, your mother will be given anaesthesia to put her into sleep and a medication that paralyze muscles, so the risk of breaking bones is rare. The patient is given oxygen before the procedure. The patient s blood pressure, heart rhythm, and medical status is monitored throughout the procedure and when she comes out of the anaesthesia. How often will my mother get ECT and for how long? 3 times per week, Mon, Wed, Fri and for 6 sessions (2 weeks); some patients may need 9 to 12 sessions.. How do you know the ECT is successful or not? We will monitor the duration of her fit. It has to be at least 25 second in duration. We will monitor her muscle movement through electrical recordings (i.e. EEG). If response is poor, we will increase the energy level 5% each time. How do you decide on the dose of ECT? By age-based dosing: Energy level = patient s age divided by 2. What tests do you include in your pre-ect work-up? Physical exam, FBC, RFT, ECG, CXR. Assess patient s dentition, especially for elderly or those who have inadequate dental care. What is the preparation for the night before the ECT? Fasting is required after 12:00 midnight and she should avoid sleeping pills if possible. What is the risk involved? ECT itself is safe. Risk is associated with anaesthesia. How does ECT affect memory? Anterograde and retrograde amnesia can occur, though in the majority of patients this does not last more than a few months following the last ECT treatment. Amnesia of events immediately preceding and following ECT treatments may be permanent (reassure the relative those memory is not important). Anterograde amnesia is always transient. In a very small number of patients, the symptoms of retrograde amnesia may be permanent. What are other common side effects? Memory problems, confusion, nausea, muscle aches and headache are the most common in the morning after the ECT. What are the risk factors associated with confusion after ECT? Old age; prior cognitive impairment; lithium; anticholinergic and bilateral placement. How would you reduce confusion after ECT? Unilateral treatment on right side of the brain, lower electrical energy, increasing the time between ECT treatments and holding off lithium or sleeping pills. What is the mortality rate associated with ECT? The mortality rate is very low, and is the same as that for general anaesthesia, which is 1 in every people. Psychotherapy 1. Cognitive behaviour therapy (CBT). The frequency of CBT is usually weekly or fortnightly. It requires 12 to 16 sessions. The cognitive therapy involves identifying negative automatic thoughts and use dysfunctional thought diary to identify pattern between the time, events, negative thoughts and resulted emotions and behaviours. The psychologist will read the diary and help patients to gently challenge the negative automatic thoughts. Behaviour therapy involves activity scheduling (for those depressed patients with psychomotor retardation), relaxation techniques (for those patients with mixed anxiety and depression). Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 13

14 Course and prognosis 2. Interpersonal therapy (IPT) IPT is held weekly or fortnightly. It involves 12 to 20 sessions. IPT is indicated for depressed patients whom precipitating factor is interpersonal problems. The psychologist closely examines interpersonal relationship and works with the patient to look at interpersonal relationship from another angle to minimise impact on the mood and use role-play to improve communication skills. 3. Brief dynamic therapy Brief dynamic therapy originates from psychoanalysis. Brief dynamic therapy is suitable for depressed patients whose predisposing factor is related to past experiences (e.g. unpleasant childhood experience with one of the parents) and these experiences have lead to the use of maladaptive defence mechanisms and affect current mood and personality development. Brief dynamic psychotherapy is contraindicated in psychotic patients. 4. Other psychotherapies include supportive psychotherapy, problem solving therapy or marital therapy depending on clinical history and case formulation. Depressive episodes may last from 4-30 weeks for mild or moderate depressive disorder to an average of around 6 months for severe depressive disorder % of patients would have depression as a chronic disorder, with signs and symptoms lasting for around 2 years. The rate of recurrence is around 30% at 10 years and around 60% at 20 years. Suicide rates for depressive individuals is 20% higher when compared to the general population. Good prognostic factors include acute onset of depressive illness, endogenous depression and earlier age of onset. Poor prognostic factors include insidious onset, old age of onset, neurotic depression, low self-esteem and residual symptoms. Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 14

15 Bipolar disorders Epidemiology International Prevalence Mean age of onset Gender ratio % (overall) 20 years. Male: female = 1: % (Bipolar I disorder) % (Bipolar II disorder). Aetiology Genetics: Family studies have demonstrated that children of parents suffering from bipolar disorder have a 9-fold increase in lifetime risk compared to the general population. The heritability of bipolar disorder is 79-93%. Twin studies indicate that monozygotic twins have 70% concordance rate and dizygotic twins have 20% concordance rate. Genes related to ion channels are implicated in the aetiology of bipolar disorder (e.g. calcium channels on chromosome 12). (Ferreira et al, 2008). Monoamine theory states that increased levels of noradrenaline, serotonin and dopamine have been linked with manic symptoms. Excitatory neurotransmitter glutamate is also implicated. The onset and first manic episode: The diagnosis is commonly delayed until early adulthood (median age of onset is in mid-20s and mean age of first hospitalisation is at 26 years) because there is abnormal programmed cell death or apoptosis in neural networks responsible for emotional regulation. The first manic episodes are often precipitated by life events such as bereavement, personal separation, work-related problems or loss of role. High expressed emotion and sleep deprivation are important precipitating factors. The relationship between depressive and manic episodes: 1 in 10 patients who suffer from a depressive episode will subsequently develop a manic episode. Monotherapy of antidepressant is a recognised precipitant of the first manic episode in patients who are predisposed to suffer from bipolar disorder. In general, depressed patients with early age of onset, family history of bipolar disorder, depressive episode occurring during postnatal period, hypersomnia and psychotic symptoms are more likely to switch to mania. Sleep deprivation and flying overnight from west to east may trigger relapse of mania. Kindling hypothesis: The persistence of neuronal damage leads to recurrence of mania without precipitating factors. This is known as kindling and subsequent manic episodes become more frequent. The episode duration remains stable throughout the course of bipolar illness Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 15

16 Organic causes of mania Cerebrovascular accident Mania is associated with rightsided cerebral vascular lesions and it is commonly associated with lesions in the frontal and temporal lobes. Endocrine causes 1. Thyrotoxicosis 2. Thyroid hormone replacement 3. Cushing s syndrome Head injury Mania is associated with right-sided hemispheric damage. Family history of mania is uncommon and patients are more irritable than euphoric. Lesions in right cerebral hemisphere are associated with mania Other CNS disorders 1. Cerebral tumour 2. Dementia 3. Epilepsy 4. AIDS 5. Multiple sclerosis Illicit substances: 1. Amphetamine 2. Cannabis 3. Cocaine Medications: 1. Anticholinergic drugs 2. Dopamine agonists (e.g. bromocriptine and levodopa) 3. Corticosteroids or anabolic steroids 4. Withdrawal from baclofen, clonidine and fenfluramine. Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 16

17 Diagnostic criteria for bipolar disorder (RATA) Appearance Increased sociability or over-familiarity Thoughts 1. Difficulty in concentration with distractibility 2. Flight of ideas or racing thought (In ICD-10, this only occurs in mania but not hypomania) 3. Inflated self esteem and grandiosity (In ICD-10, this only occurs in mania but not hypomania) 4. Constant change in plans (In ICD-10, this only occurs in mania but not hypomania) Affect: Elevation of mood and irritability Hallucination Appearance - Behaviour Thought- Speech axis Affect- Interest axis Mood congruent: voices telling the patient that he has superhuman powers. Mood incongruent: voices speaking to the patients about affectively neutral subjects. Reality axis Mania Delusion Mood congruent: grandiose delusions Mood incongruent: delusion of reference and persecution Interest increase in goal directed activity (either socially, at work or school or sexually) or excessive involvement in pleasurable activity that have a high potential for painful consequences (e.g. unrestrained buying sprees, sexual indiscretion or foolish business) Speech Increased talkativeness Behaviour 7. Increased activity and physical restlessness 8. Decreased need for sleep 9. Increased sexual energy (hypomania) / Sexual indiscretions (mania) 10. Mild overspending or other types of reckless or irresponsible behaviour (hypomania)/foolhardy and reckless behaviour with lack of awareness (mania) 11. Loss of social inhibition, resulting inappropriate behaviour Compare and contract ICD-10 and DSM-IV-TR criteria for bipolar disorder Diagnosis ICD-10 DSM-IV-TR Bipolar I Not stated Bipolar I disorder is associated with manic episodes. and II Bipolar II disorder is associated with hypomanic Hypomania Mania The duration is of several days. ICD-10 has listed specific diagnostic criteria found in mania but not hypomania (see below). The following symptoms occur in mania but not hypomania. 1. Flight of ideas or racing thought. 2. Inflated self esteem and grandiosity. 3. Constant change in plans. 4. Sexual indiscretions. 5. Foolhardy behaviour. 6. Psychotic features. episodes. At least 4 -day duration and at least 3 cognitive or biological symptoms. Associated with inflated self esteem and grandiosity, flight of idea, increase in goal directed activity (either socially, at work or school or sexually) At least 1 week duration and at least 3 cognitive or biological symptoms. Mixed episode and rapid For mixed affective episode, patient exhibits mixed affective symptoms. Both manic and depressive symptoms must be present for greater Mixed episodes refer only to patients fulfil both mania and major depression for at least 1 week. Rapid cycling as a course of bipolar disorder which Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 17

18 cycling disorders part of the current episode and symptoms can rapidly alternate. consists of at least 4 episodes of mood disturbance (manic, hypomanic and major depressive episode) in one year. Ultra-rapid cycling describes 4 or more episodes in a month and it is a rare condition. Note: Rapid cycling is more common in women, occurring later in the course of bipolar illness and antidepressants can increase the frequency of rapid cycling episodes. OSCE grid: Assess bipolar disorder You have been asked to see a 28-year-old unemployed man who has not slept for 5 day and claims to have full energy. He claims to be the President of Singapore and his plan is to unite all the world leaders to fight for poverty in developing countries. Task: Take a history to establish the diagnosis of bipolar disorder.. A. Assess mood symptoms. B. Assess biological symptoms. A1. Assess mood. How s your mood today? If I ask you to rate your mood from 1 to 10, 1 means very depressed and 10 means very happy, how would you rate your mood today? How long have you been feeling high? Do you have mood swings? How about feeling low? If so, roughly how many low or high episodes you would experience in a year? B1. Assess sleep and energy. How has your sleep been lately? What is your energy level like? Do you feel that you need much less sleep but full of energy? A2. Assess irritability. How do you get on with people recently? Do you feel that they annoy you? Do you lose your temper easily? What would you do if these people irritate you? B2. Assess appetite and weight. How has your appetite been lately? Have you lost weight recently? A3. Assess grandiosity How would you compare yourself with other people? Are you special? If yes, please tell me more. Could your special ability be a misunderstanding? Can you provide more evidence about it? Do you feel that you are at the top of the world (i.e. above all the other people)? B3. Assess sexual function and contraceptive method. I am going to ask you some sensitive questions. How has your interest in sex been lately? Do you have sex with new partners? Do you take any precaution to protect yourself (e.g. condom)? If your patient is a woman, you need to ask LMP and chance of pregnancy. C. Assess cognitive and psychotic symptoms. C1. Assess interests and plans. Could you tell me about your interests? Have you developed any new interests lately? Do you have any new plan or commitment at this moment? (for C2. Assess thought and speech. Has there been any change in your thinking lately? Have you noticed that your thoughts speed up? Do you find your thoughts C3. Assess psychotic features. When people are under stress, they have unusual experiences such as hearing a voice talking to them but cannot see the person. Do you encounter such experiences? If so, what did the voices say? How Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 18

19 example, starting a new business or investment) racing in your mind? Do your family members say that the topics in your speech change so fast and they cannot follow. many voices spoke at one time? Do you believe that you have special power or status which other people do not have? If yes, can you tell me about your special power or status? Are you very certain that you have such ability or status? D. Assess risk and insight D1. Assess risk. Have you been buying a lot of things? Have you incurred a lot of debts (e.g. credit card debts?) D2. Explore comorbidity. Do you take recreational drugs on a regular basis to get the high feelings? D3. Assess insight. Is there any reason why you encounter those experiences? Do you drive? Have you been involved in speeding or traffic offences? How about alcohol? Do you drink on a regular basis? Do you think there is a illness in your mind? For example, this illness affects your mood? Have you been in trouble with the police lately? (e.g. due to violence). If so, do you think you need treatment? When you feel sad, have you thought of harming yourself? Investigations and questionnaire - FBC, ESR. - LFT, RFT, TFT, fasting lipid, glucose and body weight measurement (as mood stabilisers are associated with metabolic syndrome). - VDRL. - Urine drug screen - Pregnancy test (for female patients who may be pregnant). - CT/MRI to rule out space occupying lesion, infarction, haemorrhage. - ECG to rule out prolonged QTc. - EEG to rule out epilepsy. The Young mania rating scale (YMRS) The YMRS is an 11-item questionnaire which helps clinicians to measure the severity of manic episodes in children and adolescents between the ages of 5 and 17 and adults. Its structure is similar to the Hamilton depression scale. Management Summary of MOH guidelines (Mok et al 2011) and NICE guidelines (UK) Acute treatment of mania Hospitalisation may be necessary in patients present with severe manic symptoms or pose serious risk e.g. violence, sexual indiscretions). Some manic patients who refuse treatment may require Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 19

20 admission under the Mental Disorder and Treatment Act. Haloperidol may be used for the treatment of acute mania. Aripiprazole, olanzapine, quetiapine, risperidone or ziprasidone may be used for the treatment of acute mania. Sodium valproate or carbamazepine monotherapy may be used for the treatment of acute mania. Lamotrigine should not be used for the treatment of acute mania, as it lacks efficacy in this area. Combination pharmacotherapy with an antipsychotic and a mood stabiliser may be used for patients showing inadequate response to mood stabiliser monotherapy. Clonazepam or lorazepam (IM or oral) may be used in the acute treatment of agitation in mania. In the emergency setting, Haloperidol (IM or oral) or olanzapine (oral) may be used in the acute treatment of agitation in mania. Acute treatment of bipolar depression. For mild depressive symptoms, it is recommended to review patients in 1 to 2 weeks without giving an antidepressant. If depressive symptoms are moderate to severe, consider adding antidepressant to a mood stabiliser. If antidepressants are to be used in combination with mood stabilisers as treatment for bipolar depression, they should be used cautiously due to conflicting evidence of efficacy and risk of inducing a manic episode. SSRI such as fluoxetine is the first line of treatment. Lithium may be used in the treatment of bipolar depression. Quetiapine monotherapy, olanzapine monotherapy or olanzapine-fluoxetine combination may be used in the treatment of bipolar depression. Monotherapy with sodium valproate or carbamazepine is not recommended in the treatment of bipolar depression due to conflicting evidence regarding efficacy. There is insufficient evidence to recommend lamotrigine monotherapy in the treatment of bipolar depression. However, it is recommended as an add-on for patients already on lithium for treatment of bipolar depression. Psychotherapy (e.g. CBT) is recommended for patients with bipolar depression. Rapid cycling and mixed state. Mood stabilisers may be used when treating mixed states. Of these, valproate and carbamazepine should be preferred over lithium, as there is more evidence for the efficacy of valproate and carbamazepine than for lithium. Non-pharmacological treatments should not be used for patients with rapid cycling bipolar disorder due to insufficient evidence. Maintenance treatment Lithium, valproate or olanzapine may be used as maintenance therapy in preventing relapse to either pole of illness in patients with bipolar disorder. Aripiprazole may be used as maintenance therapy in bipolar patients with recent manic or mixed episode. Quetiapine, in combination with lithium or valproate, may be used as maintenance therapy in Mastering Psychiatry A Core Textbook for Undergraduates Chapter 4 20